Hair cells are the sensory receptors of the internal ear, where they underlie the responsiveness of both the auditory and the vestibular systems. Each hair cell is a mechanoreceptor that responds when a sound or an acceleration applies a force to its hair bundle, a cluster of a few dozen to a few hundred mechanically sensitive filaments protruding from the cell's top surface. Because most hearing loss and many forms of dysequilibrium result from damage to hair cells, the proposed experiments are meant to reveal more about how these cells perform their essential functions. First, a combination of electron-microscopic and biophysical experiments will be used to determine whether a hair cell adapts to a prolonged stimulus by physically resetting the molecular apparatus in its hair bundle. The proposed experiments should show whether the myosin molecules thought to mediate adaptation occur at the appropriate sites and whether these molecules actually move as the hair cell adapts. A second set of experiments is meant to determine whether the hair bundle helps amplify the ear's mechanical inputs, thus augmenting the sensitivity of hearing and sharpening its frequency discrimination. In addition to providing information about the nature of the ear's amplificatory process, this investigation may indicate why hearing is vulnerable to overstimulation and whether the ear's amplifier can be protected from or regenerated after injury. In a final set of studies, genetic and molecular- biological techniques will be used to identify proteins essential to hearing and balance. More than a hundred genes are involved in heritable forms of deafness and vertigo, which affect one child in a thousand at birth and a similar proportion later in life. The zebrafish, a tractable model organism suitable for large-scale genetic analysis, will be used to identify novel genes and to determine the functions of recently discovered genes in the inner ear. After the corresponding human genes have been found, their roles in the ear and their possible involvement in human hearing loss and dysequilibrium will be examined.